Medicines from Marine Microbes

Marine species from corals and sea squirts, right down to the tiniest bacteria, are offering up chemicals that could be potential new treatments for infectious diseases and cancer.

The 'secondary metabolites' produced by these species are used as defences against infection or to outcompete other microorganisms, and humans have been exploiting them for over 50 years.

Paul Jensen from the Scripps Institution of Oceanography explains why his work on marine microbes has led to some interesting discoveries about the evolution of bacteria in the oceans, as well as new drugs, and Marcel Jaspars from the Marine Biodiscovery Centre at the University of Aberdeen explains how we go from seabed to bedside...

Sarah - Since the mid 20th century, scientists have been investigating marine species and the chemicals they produce, pointing towards new medicines, that can be used to fight diseases from cancer to sleeping sickness.

Paul - 50 years ago a group of organic chemists who were interested in marine science and interested in diving put those interests together and decided to start going to the ocean and collecting plants and animals and extracting them and studying organic compounds that they make. And that was really just a bonanza because pretty much everything that was picked up had new molecules in so it was the golden age of marine natural products chemistry.

Sarah - That was Paul Jensen, from the Scripps Institution of Oceanography, who studies marine bacteria, and whose work has led to the discovery of compounds now in trials for cancer treatment. Initially, much of the research into finding new molecules focussed on larger ocean species, but then a whole new avenue of research opened up…

Paul – As time went on there was the realization that most of the diversity in the ocean is actually microbial and noone had studies it yet in terms of looking at the chemicals and natural products that these microbes makes. And so that really ushered in the next wave of ocean exploration in terms of bioprospecting, if you want to call it that, but I will call it natural products research.

Sarah - So why do species, from bacteria to corals, actually produce these compounds?

Marcel - Initially the invertebrates, the sponges, soft corals and sea squirts are interesting because they have no other obvious other means of defense. So we’re looking at them because they have a chemical defense system without an alternative immune system perhaps, and these compounds tend to be very active.

Sarah - That’s Marcel Jaspers, from the University of Aberdeen, who runs the Marine Biodiscovery Centre, which actively looks for potentially medically useful chemicals produced by marine species. As we just heard, the larger species being investigated, the sponges and corals, possibly use the active chemicals they produce as a defence mechanism. But what about bacteria? Paul Jensen…

Paul – in some cases these molecules may be produced for defensive purposes. They may be to compete and defend a resource from other competing microbes but it can also be more complicated than that. They can be signalling molecules, there’s a lot of chemical communication going on in the ocean.

In fact this is a really exciting forefront of the field right now because people are realizing right now that the language that microbes communicate in is chemistry. And understanding how and why they produce these molecules and that process of communication is really an exciting part of where all of this is going.

Sarah - So if marine organisms produce these compounds as defence against infections or to outcompete other microorganisms, it’s a logical step to guess that they could be effective treatments for infectious diseases.

Another exciting, non-medical part of the research is that it’s giving us clues to the evolution of bacteria in the oceans…

Paul – when we look at these organisms one of the most fundamental things that distinguishes what we think are different groups are these molecules that they make. And that’s been a challenge in microbiology from the early days is that in the case of bacteria they don’t really look like much, and in many cases its hard to distinguish them and so now we have genomics and we can sequence their genomes and that gives us a complete blueprint of who they are. That tells us everything that they’re capable of doing.

And when we look at the genomic level and we compare groups that we think are different but closely related what we see is that it’s mostly in terms of these molecules of chemicals that they’re making. So we think that the ability of bacteria to produce these, what we call secondary metabolites, maybe fundamentally important in defining who they are.

Sarah - And it’s this kind of research, finding out who the bacteria are phylogenetically, as well as why they produce these compounds, that is the focus of Paul’s work. The potential medical benefits are for him, an exciting side effect.

But once you extract the chemicals that you think might have some kind of useful medical action, how do you decide what to test them against? It’s very much down to the research interests of the lab involved, and any industry collaborators, but as Marcel Jaspers explains, it helps to narrow it down…

Marcel – so first of all you need to know what your best bets are. So in natural products the things that we look at mainly are cancer, inflammation, infectious diseases, and parasitic diseases. That’s where they’ve been proven to work the best.

Most of the drugs that are coming forwards through the pipeline are for cancer. There’s painkillers on the market from sea snails. So we are really thinking about how to get from seabed to bedside, as people sometimes say.

The answer is that there’s really a lot of effort needed to go from the small scale, from the milligram quantities that we can isolate, to the kg scales that are needed for clinical trials.

Sarah - And it’s been a very successful field. Several molecules extracted from microbes, sea squirts and sponges have already undergone successful trials against cancer. Each of the compounds works in a slightly different way – by stopping cells from dividing or disrupting the cell cycle or blood supply to the tumour.

But, as we heard from Marcel, the main challenge is one of scale – how do we produce enough of the compound to use in a clinical trial, and then what happens if it ends up being rolled out as a treatment to the public? Isolating the gene that codes for the compound you’re interested in, and inserting that gene into bacteria that will then produce it en masse is one solution.

This is one benefit to looking in bacteria for these compounds in the first place. Another benefit comes from a conservation point of view, reducing the pressure on larger organisms that might be collected for this kind of research. But, we shouldn’t forget about the conservation of the bacteria either…

Paul – a lot of people don’t think about the conservation side of microbes. And so, there’s a couple of points here. One, in the early days when people were going to and collecting macroorganisms there’s some issues there from a conservation side, because if you find something it might come from a rare organism, and oftentimes these molecules are very complex and they’re not easy to synthesize in the laboratory and so you have to go to nature to collect them.

So the idea of working with microbes is attractive because you can culture them, you don’t have to go back to nature to get them over and over again. So it’s a renewable resource. So that’s very attractive.

But secondarily this point about what’s the diversity that’s out there now, and how is that diversity changing in response to the impacts that humans have on the environment. And without question it is changing. We don’t know if that’s good or bad from the perspective of natural product discovery but my hunch is that it’d be bad because most likely the way things are changing is we’re going to see less diversity over time. So that’s actually a very important consideration that’s often not even discussed when people think about conservation and diversity issues.

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